Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds and (IC = 51.84–74.36 nM) being more potent than SAHA reference drug (IC = 91.73 nM). Additionally, the most potent derivatives were further assessed for their cytotoxic activity against two human leukemia cells. Hydantoin derivative was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells was also screened against different HDAC isoforms. was superior to SAHA against HDAC1. Cell-based assessment of revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.

中文翻译：

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以 (Thio)Hydantoin 作为锌结合部分发现新型苯并咪唑衍生物作为有效的 HDAC 抑制剂对抗白血病：设计、合成、酶抑制和细胞机制研究

基于组蛋白脱乙酰酶 (HDAC) 抑制所需的成熟药效团特征，设计并合成了一系列易于合成的新型苯并咪唑连接的 (硫代)乙内酰脲衍生物作为 HDAC6 抑制剂。所有目标化合物均以纳摩尔水平有效抑制 HDAC6，且化合物 (IC50 = 51.84–74.36 nM) 比 SAHA 参考药物 (IC50 = 91.73 nM) 更有效。此外，还进一步评估了最有效的衍生物对两种人类白血病细胞的细胞毒活性。乙内酰脲衍生物对 MOLT-4/CCRF-CEM 白血病细胞的作用分别与 SAHA 等效/优于 SAHA，并且针对不同的 HDAC 亚型进行了筛选，证明其对非癌性人类细胞的安全性优于 SAHA。对抗 HDAC1 的效果优于 SAHA。基于细胞的评估揭示了显着的细胞周期停滞和细胞凋亡诱导。此外，蛋白质印迹分析显示 CCRF-CEM 细胞中乙酰化组蛋白 H3、组蛋白 H4 和 α-微管蛋白的水平增加。此外，对接研究揭示了标题化合物螯合位于 HDAC6 活性位点内的 Zn 的能力。此外，理化性质的计算机评估表明，目标化合物在药代动力学方面是有前途的候选化合物。